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The first detailed study of the clinical features, hereditary nature and pathology of muscular dystrophy is attributed to Edward Meryon, an English physician, who published his findings in 1852. Yet it was more than 130 years later that the responsible gene for the commonest form of dystrophy, Duchenne muscular dystrophy, was identified and characterised. Subsequently the genes for many other forms of dystrophy have been identified, and it is estimated that there are now approaching 40 such disorders, though some of these are very rare. However once the gene for Duchenne dystrophy had been identified and its protein product, dystrophin, found to be localised to the muscle membrane, many thought it would not be very long before the details of the pathogenesis of this disorder would be understood, with the possibility of finding an effective treatment. But clearly there is still a great deal we do not understand.
The structure and function of the dystrophin-glycoprotein complex still exercises the attention of biochemists. It is now clear that many other proteins interact with this complex. Some components, such as syntrophin, may not themselves be associated with any specific form of dystrophy yet may still play a key role in cell signalling. In certain forms of dystrophy the defective proteins have been found to be associated not with the dystrophin-glycoprotein complex but either lie outside the complex (e.g., laminin A2 chain of merosin) or even be associated with the inner nuclear membrane (lamins A/C and emerin). Furthermore in certain dystrophies primary defects of glycosyltransferase activity have been reported. Finally myotonic dystrophy (a multi-system disease and therefore some would argue not a ‘true’ dystrophy), oculopharyngeal dystrophy and facioscapulohumeral dystrophy are each associated in their different ways with tandem repetitive DNA sequences.
In view of the considerable variation in their clinical features, genetics and molecular pathologies, one questions whether the all-embracing term ‘dystrophy’ continues to be relevant. Perhaps a solution might be to base nomenclature on specific protein defects such as dystrophinopathies, sarcoglycanopathies, and laminopathies.
An unexpected finding in certain dystrophies, but now reported in some other conditions though not to the same extent, is the phenomenon of very different phenotypes being generated by different alleles. For example, different mutations of the LMNA gene have now been shown to account for two different forms of dystrophy as well as for no less than six other clinically distinct disorders. This finding could have important implications for any approach to therapy in future.
A clear understanding of pathogenetic processes could one day lead to the finding of a drug which in some way interferes with these processes and thereby be therapeutically effective. Meanwhile attention has turned to the possibility of various forms of gene therapy and stem-cell therapy. In gene therapy approaches currently being pursued include using a viral vector for gene replacement. However in view of the recently reported cases of ‘insertional mutagenesis’ (following gene therapy for severe combined immunodeficiency resulting in T-cell leukaemia), several other approaches are being pursued: for example, appropriate antisense oligonucleotides to effect exon skipping and the possibility of the upregulation of a compensatory gene product. With regard to the latter approach, in Duchenne dystrophy upregulation of utrophin (or perhaps ADAM-12 or calcineurin), may compensate for the deficiency of dystrophin and a search is ongoing to find a possible drug to do this in patients. Stem-cell therapy (as opposed to myoblast transplantation) offers an attractive alternative but to be therapeutically effective a means will have to be found to improve the efficiency of vascular delivery.
There is no doubt that the study of the muscular dystrophies in recent years has been exciting and rewarding. It has attracted the attention of many investigators of international repute, and this is reflected in the various contributions to this volume. One is reminded of what Bertolt Brecht expressed so aptly: ‘Beauty in nature is a quality which gives the human senses a chance to be skilful’. less